The War Against Prostate Cancer Biology Essay

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Death rate caused by the different types of cancer has not changed considerably since the "War on cancer" (this term refers to the attempt to obtain a successful method to treat cancer by augmented research towards improving the understanding of tumour nature and also developing more efficient treatments for the cancer, for example by using the idea of targeted drug therapy) was started approximately 40 years ago. Huge amount of money have been invested in cancer research, but the improvement toward a cure has been clearly slow. In spite of the fact that, anticancer drugs are more efficient in early stages of the disease, the late stages are usually resistant to the same kind of treatment. In order to eliminate or at least reduce cancer metastasis, it is essential to understand this shift in the cellular behaviour (Benhar et al., 2002).

Prostate cancer is a significant health care problem in the entire world due to its high incidence and mortality, the costs associated with its detection and treatment, and the fact that no consensus exists on what constitutes the best form of treatment for any stage of this disease. Excluding superficial skin cancers, prostate cancer is the most common malignancy afflicting men in the entire world. The occurrence of this kind of cancer cases rose significantly in the early 1990's. The main reason for this figure was probably because of the advances in prostate screening and detection. Approximately 550,000 new patients were estimated to suffer from prostate cancer worldwide each year. On the other hand mortality rate caused by prostate cancer have remained unchanged (DeVita, 2005).

It is becoming increasingly recognized that cancerous cells produce a large quantity of hydrogen peroxide and upon this idea a novel method to treat prostate cancer has been investigated. The finding that tumour cells themselves can generate reactive oxygen intermediates may assist in explaining why some tumour cells are resistant to oxidative cytolysis. During respiration different types of reactive oxygen species are generated from the mitochondria. Low levels of these species play an important role in cellular signalling and cell proliferation. Hyper activation of transcription factors (NF-kB and AP-1) shows to be one functional role of elevated levels of the oxidizing species during tumour progression (Polytarchou et al., 2005).

Hydrogen peroxide serves as a strong oxidant like the other members of Reactive Oxygen Species (ROS) leading to destruction in many parts of the cell of which they are a part. In presence of iron, hydrogen peroxide converted to a hydroxyl radicals. These radicals work by damaging the DNA leading to a programmed cell death (apoptosis). One of the molecules that have been documented to be a possible source of iron to react with hydrogen peroxide is Ferrocene (Kong et al., 2009).

In spite of the fact that, mutation of the testosterone receptor itself may be one of the factors leading to prostate cancer, testosterone can be used as a part of a targeted drug for treating prostate cancer.

This proposal has been designed to make a complex of testosterone and Ferrocene. Testosterone has the ability to be recognised by a particular receptor on prostate glands and by making this complex, testosterone will works as a specific carrier for Ferrocene to prostate cells. In this work we hope to make this complex with the ability to reach the prostate as an un-reacted drug. Because of the fact that, prostate cancerous cells have a higher amount of hydrogen peroxide than the normal prostate cells, the complex will react more specifically with the cancerous ones.

2- Introduction:

Prostate cancer is one of the commonest types of malignant tumour in men that takes place in the prostate gland. Almost in all kinds of cancer, if it is advanced or left untreated in early periods, it can ultimately spread to other organs through the blood and lymph fluid. Fortunately, if prostate cancer compared with other forms of cancer, it tends to be slowly growing. Prostate cancer is one of the most common cancers in men. It is responsible for approximately 25% of newly identified cases of cancer in the United Kingdom. Approximately 75% of prostate cancer patients have been found in the developed countries (Votron et al., 2004).

Prostate cancer is a disease of the elderly. Around the world, three quarter of cases occur in men aged ≥ 65 years. It is therefore more common in countries with a higher proportion of elderly men in their population. Prostate cancer is unique among solid tumours in that it exists in two forms: a histologic or latent form, which can be identified in approximately 30% of men older than 50 years and 60% to 70% of men older than 80 years, and a clinically evident form which affects approximately one in six men in the developed countries (Parkin et al., 2001). The next figure represents the death rate caused by prostate cancer in the entire world

Mortality from prostate cancer: age standardised rate (world) (all ages).

Reprinted from (Parkin et al., 2001)

Regardless of the advances in the prevention and early detection, advancements in surgical technique and improvements in adjuvant radio-therapy and chemotherapy, the ability to cure many patients with prostate cancer remains mysterious. Understanding the biological processes of prostate cancer is an important aspect in the development of a new therapeutic agent to be used for treating this kind of cancer. To achieve this target successfully, the researchers in this area require to get access to animal as models, cell line and biospecimens (Chung, 2007).

There are many risk factors contributing in developing prostate cancer. Some examples of these factors are: age, ethnicity, dietary factor and genetic factors. Other factors include obesity and smoking (Malila, 2006). Dietary manipulations have also gained much interest and Epidemiologic studies have shown that the incidence of clinically significant prostate cancer is much lower in parts of the world where people eat a predominantly low fat, plant based diet. In addition, migrant studies demonstrate that when men from a low risk country move to a high risk country such as the United Kingdom and begin eating a Westernized diet, their rates of prostate cancer increase several fold and approach that of the host country. However, which component of a certain diet increases prostate cancer risk remains ambiguous. Researchers have suggested that fat, soy, green tea, selenium, and vitamins, among others, as modifiers of prostate cancer risk (Krayalcin, 1997).

Inherited forms of prostate cancer tend to develop at an earlier age compared with irregular cases, although differences in terms of biological potential between inherited and irregular forms of disease are less apparent (Steven et al., 1998).

The real causes for this type of cancer are basically mysterious and the outlook for this cancer is commonly acceptable in spite of the fact that it being moderately difficult to treat. This is because of the fact that, almost all cancer types tend to progress very quickly except prostate cancer which progress extremely gradually. This kind of cancer can take up to 15 years to spread (metastasis) from the prostate cancerous cells to other body parts especially for the bones. In such situation where cancer has spread the only available way to control the case is androgen deprivation. Androgen deprivation therapy has been the mainstay of locally advanced and metastatic prostate cancer treatment over the last five decades. The concept of this treatment is based on the fact that androgens play a crucial role in promoting proliferation and migration of prostate cancer cells while inhibiting apoptosis. Androgen deprivation therapy can be administered in the form of surgical castration, gonadotropin releasing hormone (GnRH) receptor agonists or androgen receptor (AR) antagonists. However, it must be taken into account that androgen ablation only lasts for 2 years in average. Cancer patients invariably develop castration resistant prostate cancer (CRPC) (Kohli and Tindall, 2010).

Almost in most of the cases, the natural life span of men's will not affected by prostate cancer. If this kind of cancer has metastasised to the bones it can't be treated, and the treatment is only fixed on extending patient life as possible and reducing pain feeling associated with this cancer. Just in England and Wales approximately 10,000 men die from prostate cancer every year (NHS, 2010).

Many pharmaceutical companies work hard to develop a new drug to treat prostate cancer with fewer side effects of the available known drugs, because of the fact that, prostate cancer is one of the most common cancers between men. This gland is walnut sized situated in front of the rectum and immediately under the bladder. Even though this gland is fabricated by numerous types of cells, most of cancers that develop in the prostate take place in the glandular cells. Cancer of gland cells is known as adenocarcinoma. The main function of the glandular cells of the prostate is to make a viscous liquid to facilitate the function of the urethra during ejaculation. This liquid is considered as one of the important element of the seminal liquid, which nourishes the sperm. Prostate secretions lead to elevation in the pH of the seminal fluid which in turn lead to neutralization of the acidity of the woman vagina during the intersexual course (Karen et al., 2010).

Because of the slow development of the disease, the majority of prostate cancers are unlikely to kill the patient. Several studies have reported that, the long term outcome for patients with a localized prostate cancer managed expectantly over a period of more than 20 years, also they confirmed that most patients with an early stages of prostate cancer have a favourable outcome even without any attempt at cure (Albertsen, 2005).

Prostate cancer rarely causes symptoms until it is in the advanced stage. Thus, suspicion of prostate cancer resulting in a recommendation for prostatic biopsy is generally often elevated by irregularities detected using digital rectal examination (DRE) or by serum prostate specific antigen (PSA) elevations. It is highly recommended to do prostate biopsy for all patient who have digital rectal examination irregularities, in spite of the serum prostate specific antigen level, because 25% of the patient with this type of cancer have a normal prostate-specific antigen level (Kirby et al., 2000).

Prostate cancer diagnosis should always be supported by the histological assessment of tissue samples, most often obtained at a prostate biopsy. Sometimes prostate cancer may be found incidentally in a pathological specimen removed during surgery for benign prostatic hyperplasia or for urethral malignancy. Sometimes the diagnosis of prostate cancer may be suspected and confirmed only at biopsy. Neither clinical tests nor symptoms alone can fully confirmed a diagnosis of prostate cancer (Christopher et al., 2001).

Androgens play an essential function in the pathogenesis of prostate cancer. During puberty, increasing androgen levels result in extensive morphological changes to the gland, giving rise to the complex glandular structure seen in the adult. Maintenance of the adult prostate is under continuous androgenic control, and androgen deprivation as a result of castration causes apoptosis of prostatic epithelium. However, later in life androgens play a significant role in prostate disease pathogenesis, particularly benign prostatic hyperplasia and prostate cancer. The polymorphism of genes involved in the metabolism of androgens is thought to be some of the susceptible factors for the disease. These susceptibility genes may be of high or low penetrance. The low penetrance genes although pose low individual risk could alter predisposition to prostate cancer (Shaw and Prowse, 2008).

A group of researchers have studied the connection among polymorphisms in some genes such as androgen receptor (AR) and prostate specific antigen (PSA), and prostate cancer and benign prostatic hyperplasia (BPH). They found that androgen receptors contain polyglutamine (CAG) repeat sequences whose variation is considered to be a contributing factor for prostate cancer susceptibility. Shorter polyglutamine repeat lengths < 20 have been associated with higher prostate cancer risk. Shorter polyglutamine repeats have also been associated with benign prostatic hyperplasia (Das et al., 2008).

1, 25-dihydroxyvitamin D (1,25D), also known as calcitriol, is the active form of vitamin D. 1,25D has been shown to promote differentiation and inhibit the proliferation and invasive potential of human prostate cancer cells. Prostate cells express vitamin D receptors (VDR), which mediate the function of 1,25D. Ingles and associates found that "the presence of a single long poly A allele (i.e., L) conferred a 4.6-fold increased risk of prostate cancer" (Bai et al., 2009).

Steroidal androgens and oestrogens have been used as medicines both in the intact and derivative forms. The most important kind of androgen for the prostate is Dihydrotestosterone (DHT), which is synthesized naturally inside the human body from testosterone by 5α- reductase types 1 and 2. As a result, inhibition of these two enzymes has a potential role in treating both benign prostate hyperplasia and prostate cancer. Finasteride, was the first drug to be approved by the Food and Drug Administration for treating benign prostate hyperplasia, because it has an ability to inhibit 5α- reductase type 1. Further development in this area of research lead to the discovery of Dutasteride, which is used for the same indication but it is more effective and has a longer duration of action than the previous drug because it is capable to inhibit both types of 5α- reductase. In spite of the fact that, both of these two medicines are well tolerated, they have some side effects such as irreversible sexual dysfunction, impotence, abnormal ejaculation, decreased ejaculatory volume and abnormal sexual function (Rittmaster, 2008).

Finasteride (Proscar®) Dutasteride (Avodart®)

There are few choices to treat cancer for example chemotherapy, antibiotics and radiotherapy. The most frequent one of these is the chemotherapy. Most of the drugs that are used to treat cancer are not specific for cancer cells for this reason most of them lead to many side effects. The side effects of using chemotherapy can be classified to temporary and long term side effects. The former one is not scaring because most of them are not life threatening for example: hair loss, dry mouth, mouth sores, difficulty or pain in swallowing, nausea, vomiting, diarrhoea, constipation, fatigue, bleeding, loss of appetite and changes with taste are a few of the temporary disadvantages (Kodama et al., 2008). On the other hand, long term treatment with chemotherapy leads to severe side effects for instance: bone marrow suppression, damage to the nerves, especially in the hands and feet, renal and heart dysfunction, increase patient susceptibility to have stroke, infertility and teratogenicity (Anderson et al., 1995).

The use of chemotherapy is an important approach in cancer therapy. Nevertheless, its use is so limited by plenty of disadvantages, such as low concentration of the drug at the intended site, general cytotoxicity, low selectivity for cancerous tissues over normal ones especially for the fast dividing cells for example hair, gastrointestinal epithelium and bone marrow, and the appearance of drug resistant tumour cells. On the other hand, targeted delivery of anticancer drugs may be one of the successful techniques to overcome the mentioned problems of using chemotherapeutic agents as a first choice to treat the different kind of cancers because these targeted agents reduce the progression of cancerous units because it has the ability to interfere with some particles essential for the progression and growth of the cancer. This delivery can be accomplished by many techniques such as gene directed enzyme prodrug therapy (GDEPT, also known as suicide gene therapy), virus directed enzyme prodrug therapy (VDEPT), and antibody directed enzyme prodrug therapy (ADEPT) (Xu and McLeod, 2001).

The biochemistry of cancers is enormously complex, but it has generally been accepted that the free radicals play many important roles, notably in carcinogenesis and tumour promotion. The high level of hydrogen peroxide is one of the unique features for cancerous cells. This feature may be manoeuvred to act as a prodrug for treating the different kinds of cancer. By utilizing the idea of treating cancer using prodrug or targeted delivery, the side effects that caused from using many chemotherapeutics agent can be eliminated.

Unnecessary iron ingestion as of either foodstuff or dietary increments can be a source of reactive oxygen species. Iron, which is one of the most widespread metals in the body, reacts with H2O2 and catalyses the production of extremely reactive hydroxyl radicals, in this manner the oxidative stress is increased, and this consequently increases free iron concentrations by the Fenton and Haber-Weiss reaction as the following reaction:

Fe3+ + H2O2 → Fe2+ + OH· + H+

Fe2+ + H2O2 → Fe3+ + OH· + OH−

Cancerous cells as mentioned before produce more hydrogen peroxide than normal ones, for this reason it is more affected by this oxidative stress than normal cells (Choi et al., 2008).

Metal complexes are promising compounds for the design of new anticancer agents. The conjugation between organic medicinal substance and metals are of a great importance and these compounds are known as organometallic compounds. The significance of organometallics can be observed by their occurrence in most of the living organisms. This kind of chemistry "involves the use of metal ligands bound to organic carbon based structures. Such structures allow the carbon bound metal ligands to be thermodynamically and kinetically to be contained" (Guo, 1998). There are many chemotherapeutic drugs classified as organometallic compounds such as cis-diamminedichloroplatinum (II) (cisplatin) and cis- diammine (cyclobutane-1,1- dicarboxylate-O,O') platinum (II) (carboplatin), which are the first antitumor drugs in clinical use. Biological studies have shown that DNA is the primary cellular target for these metal based drugs. Intensive efforts of various research groups in recent years have contributed significantly toward an improved understanding of the mechanism of the antitumor activity of platinum complexes. However, significantly less is known about the antitumor mechanisms of non-platinum metal based complexes (Guo, 1998).

In order to overcome some of the clinical problems associated with the relatively limited activity of cisplatin and carboplatin against the broad spectrum of human malignancies, acquired resistance, and side effects, a lot of new non-platinum metal based anticancer complexes have been developed. Among them, some compounds containing Ferrocene. Ferrocene and its derivatives have been involved in various chemotherapeutic studies. It was discovered in 1951 and synthesized by chance as most of compounds at that time. This discovery led to expansion in studying the organometallic compounds and searching for new agents. Because of the fact that ferrocenyl moiety have enough stability in solutions, aerobic medium, can be connected to a variety of molecules and the encouraging electrochemical characteristics have made this moiety and its derivatives extremely common compounds to be used in the medicinal field (Keister et al., 2007).

One of the best known examples of Ferrocene compounds is Hydroxyferrocifens family which is proposed to treat breast cancer. This family have two actions, the first one is endocrine modulating characteristics due to the presence of tamoxifen skeleton and the second action is cytotoxicity due to the presence of ferrocene moiety. To date, the most efficient compound in terms of pure cytotoxicity is the ferrocenyl diphenol compound which shown in the next figure:

This compound exhibits a high antiproliferative activity in vitro against both hormone dependent and independent breast cancer cells (Buriez et al., 2008).

Ferrocene derivatives can also be used as an anti-malarial drug. The bacteria Plasmodium falciparum is increasingly becoming resistant to the drug Chloroquine (CQ) and the other kind of anti-malarial agents. Therefore, a new moiety had been developed known as Ferroquine. This new drug is an analogue based on the Chloroquine structure. It had been discovered that Ferroquine was more potent then the Chloroquine model and was able to act on parasites resistant to Chloroquine (Pradines et al., 2001).

A group of researcher have synthesized seven novel derivatives of Ferrocene with different effects on the human body. One of these compounds is 2- ferrocenylidene-17β- hydroxy androst-4-en-3-one, which has an anti-proliferative activity and it is structure as shown in the next figure:

Another compound has been synthesized by the previous group is 16-ferrocenylidene-17β- hydroxy androst -1,4-diene-3,17-dione, which has an anti-inflammatory activity and it is structure as shown in the next figure:

The observed similarity of oestrogen and androgens with respect to hormonal activity has lead to the researchers exploring possible methods in which Ferrocene could be incorporated within the prostate cancer treatment framework. Hydrogen peroxide can react with a number of chemical agents producing very active hydroxyl radicals. These radicals can damage the DNA of cancer cells thus triggering the mechanisms of cell death (apoptosis). Ferrocene is one of the compounds capable of inducing the apoptosis in cancer cells via the free radical mechanism. However, Ferrocene on its own has no affinity for cancer cells and therefore cannot be specifically delivered to these targets. The aim of this project is to prepare the Ferrocene-testosterone conjugate capable of entering prostate cancer cells and inducing apoptosis in these cells. Unlike free Ferrocene, the conjugate should be preferentially taken up by prostate cancer cells, since these cells possess significant amounts of the testosterone receptors. Once inside the cell, the compound can activate the production of free radicals by reacting with excessive amounts of hydrogen peroxide. The damage to actively dividing normal cells should be limited due to the absence of H2O2 in these cells. This project involves a novel synthetic work.

Here is a new method of synthesis of Ferrocene conjugated testosterone which could have the potential ability to exert its Apoptosis effect on cancer cells.